The present invention provides oxazinocarbazole derivatives having a ring connecting position 8 (C-8) and position 9 (N-9), and more specifically, provides compounds of formula (I) described herein below. These compounds are 5-HT ligands, and are useful for treating diseases wherein modulation of 5-HT activity is desired.
Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic, and the serotonergic neurotransmitter systems. For example, serotonin has been implicated in a number of diseases and conditions which originate in the central nervous system. These include diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia, and other bodily states. R. W. Fuller, Biology of Serotonergic Transmission, 221 (1982); D. J. Boullin, Serotonin in Mental Abnormalities 1:316 (1978); J. Barchas, et al., Serotonin and Behavior, (1973). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory, and electrophysiologic effects.
As a result of the broad distribution of serotonin within the body, there is a tremendous interest in drugs that affect serotonergic systems. In particular, receptor-specific agonists and antagonists are of interest for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer""s disease, Parkinsonism, and Huntington""s chorea), and chemotherapy-induced vomiting. M. D. Gershon, et al., The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); P. R. Saxena, et al., Journal of Cardiovascular Pharmacology, 15:Supplement 7 (1990).
The major classes of serotonin receptors (5-HT1-7) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203. Recently discovered information regarding subtype identity, distribution, structure, and function suggests that it is possible to identify novel, subtype specific agents, having improved therapeutic profiles (e.g. fewer side effects).
For example, The 5-HT6 receptor was identified in 1993 (Monsma et al. Mol. Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem. Biophys. Res. Com. 1993, 193, 269-276). Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor with high affinity and this binding may be a factor in their profile of activities (Roth et al. J. Pharm. Exp. Therapeut. 1994, 268, 1403-1410; Sleight et al. Exp. Opin. Ther. Patents 1998, 8, 1217-1224; Bourson et al. Brit. J. Pharm. 1998, 125, 1562-1566; Boess et al. Mol. Pharnacol. 1998, 54, 577-583; Sleight et al. Brit. J. Pharmacol. 1998, 124, 556-562). In addition, the 5-HT6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al. Life Sciences 1998, 17/18, 1473-1477). Together these studies and observations suggest that compounds that antagonize the 5-HT6 receptor will be useful in treating disorders of the central nervous system.
Compounds of the present invention are 5-HT ligands (e.g. receptor-specific agonists or antagonists). Thus they are useful for treating diseases wherein modulation of 5-HT activity is desired. Specifically, the compounds of this invention are useful in the treatment of psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, anxiety, migraine headache, drug addiction, convulsive disorders, personality disorders, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, and sleep disorders. The compounds of this invention are also useful to treat psychotic, affective, vegetative, and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs. This last action will allow higher doses of antipsychotics to be used and thus greater antipsychotic efficacy to be obtained as a result of a reduction in side effects. The compounds of this invention are also useful in the modulation of eating behavior and thus are useful in treating excess weight and associated morbidity and mortality.
International Publication No. WO97/45427 discloses pyridocarbazole derivatives having a highly selective cyclic GMP-phosphodiesterease inhibitory effect.
International Publication No. WO95/11245 discloses tetracyclic indole derivatives which have a selective antagonism against intestinal 5-HT3 receptors and are useful for preventing or treating digestive tract disorders such as irritable bowel syndrome and diarrhea.
Abstracts of SU-256776-S, SU-252342-S and SU-255278-S disclose 1,2-dihydropyrazino carbazoles useful as intermediates in the synthesis of biologically active compounds.
European Patent Application EP 377238 discloses annelated indolo [3,2-c] lactam derivatives having an antagonistic activity on 5-HT receptors. The compounds can be used for the treatment gastrointestinal system disorders, central nervous system disorders, cardiovascular disorders, respiratory system disorders, and for alleviating or preventing withdrawal symptoms which are induced by abuse of drugs.
European Patent Application EP 344015 discloses tetracyclic ketones useful in the treatment of psychotic disorders, anxiety, nausea, and vomiting in which a cyclohexanone ring system is fused to an indole system.
European Patent Application EP 297651 discloses tetracyclic ketones useful as antagonists of serotonin receptors in which a cyclohexanone ring system is attached to an indole system.
The present invention provides a compound of formula I 
or a pharmaceutically acceptable salt thereof wherein
R1 is
(a) H,
(b) halo, or
(c) C1-6 alkyl;
R2 is
(a) H,
(b) halo,
(c) xe2x80x94OH,
(d) xe2x80x94CN,
(e) xe2x80x94CF3,
(f) xe2x80x94O(C1-6)alkyl,
(g) C1-6 alkyl,
(h) C3-6 cycloalkyl,
(i) xe2x80x94NR5R6,
(j) xe2x80x94CONR5R6,
(k) xe2x80x94SO2NR5R6,
(l) xe2x80x94COOR7, or
(m) phenyl, optionally substituted with halo, OH, O(C1-4) alkyl, or C1-6 alkyl;
R3 is
(a) xe2x80x94(CH2)mxe2x80x94NR8R9 wherein the xe2x80x94(CH2)mxe2x80x94chain may be substituted with one or two C1-6 alkyl or C3-6 cycloalkyl;
R4 is
(a) aryl, or
(b) heteroaryl;
aryl is phenyl or naphthyl, optionally substituted with one or more R10;
hetetoaryl is a radical of a five- or six-membered monocyclic aromatic ring having one or two heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X), or a radical of a nine- or ten-membered ortho-fused bicyclic aromatic ring having one, two or three heteroatoms each selected from the group consisting of oxygen, sulfur, and N(X); wherein X is absent, H or C1-4 alkyl; wherein carbon atoms of heteroaryl may be substituted with one or more R10;
R5 and R6 is independently
(a) H,
(b) C1-6 alkyl, or
(c) C3-6 cycloalkyl;
R7 is
(a) C1-6 alkyl, or
(b) (C1-3 alkyl)-phenyl wherein phenyl may be substituted with R10;
R8 and R9 is independently
(a) H,
(b) C1-6 alkyl,
(c) C3-6 cycloalkyl,
(a) C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR11R12, or xe2x80x94CO2R5,
(e) xe2x80x94CHO, with the proviso that only one of the R8 and R9 is CHO, the other one is hydrogen,
(f) xe2x80x94(CH2)mxe2x80x94phenyl wherein the phenyl may be substituted with halo, or
(g) R8 and R9 taken together with the nitrogen to which they are attached form a five-, six-, or seven-membered heterocyclic ring wherein the heterocyclic ring optionally has one to two additional heteroatoms selected from the group consisting of oxygen, sulfur and N(Y) and wherein the carbon atoms of the heterocyclic ring is optionally substituted with one or two R13;
Y is absent or R14;
R10 is
(a) halo,
(b) xe2x80x94OH,
(c) xe2x80x94CN,
(d) xe2x80x94CF3,
(e) xe2x80x94O(C1-6)alkyl,
(f) C1-6 alkyl,
(g) C3-6 cycloalkyl,
(h) xe2x80x94NR5R6,
(i) xe2x80x94CONR5R6,
(j) xe2x80x94SO2NR5R6,
(k) xe2x80x94COOR7, or
(l) phenyl, optionally substituted with halo, OH, O(C1-4) alkyl, or C1-6 alkyl;
R11 and R12 is independently,
(a) H, or
(b) C1-4 alkyl;
R13 is
(a) C1-6 alkyl,
(b) C3-6 cycloalkyl,
(c) C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR10R11, or xe2x80x94CO2R5,
(d) xe2x80x94OH, or
(e) oxo (xe2x95x90O);
R14 is
(a) H,
(b) C1-6 alkyl,
(c) C3-6 cycloalkyl,
(d) C2-4 alkyl substituted with xe2x80x94OH, xe2x80x94O(C1-4 alkyl), xe2x80x94O(C1-4 alkyl)xe2x80x94NR10R11, or xe2x80x94CO2R5,
(e) xe2x80x94COOR7,
(f) xe2x80x94OH, or
(g) oxo (xe2x95x90O);
and m is 2, 3 or 4.
The present invention further provides a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In preferred embodiments, the composition preferably comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The present invention further provides a method for treating a disease or condition in a mammal wherein a 5-HT receptor is implicated and modulation of a 5-HT function is desired comprising administering to the mammal a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The present invention further provides a method for treating a disease or condition in a mammal wherein a 5-HT6 receptor is implicated and modulation of a 5-HT6 function is desired comprising administering to the mammal a therapeutically effective amount of a compound of formula III, or a pharmaceutically acceptable salt thereof;
The present invention further provides a method for treating or preventing diseases or disorders of the central nervous system comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal. Diseases or disorders for which a compound of formula I may have activity include, but are not limited to the following: obesity, depression, schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, a stress related disease (e.g. general anxiety disorder), panic disorder, a phobia, obsessive compulsive disorder, post-traumatic-stress syndrome, immune system depression, a stress induced problem with the urinary, gastrointestinal or cardiovascular system (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, sexual dysfunction in a mammal (e.g. a human), addictive disorder and withdrawal syndrome, an adjustment disorder, an age-associated learning and mental disorder, anorexia nervosa, apathy, an attention-deficit disorder due to general medical conditions, attention-deficit hyperactivity disorder, behavioral disturbance (including agitation in conditions associated with diminished cognition (e.g., dementia, mental retardation or delirium)), bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conduct disorder, cyclothymic disorder, dysthymic disorder, fibromyalgia and other somatoform disorders, generalized anxiety disorder, an inhalation disorder, an intoxication disorder, movement disorder (e.g., Huntington""s disease or Tardive Dyskinesia), oppositional defiant disorder, peripheral neuropathy, post-traumatic stress disorder, premenstrual dysphoric disorder, a psychotic disorder (brief and long duration disorders, psychotic disorder due to medical condition, psychotic disorder NOS), mood disorder (major depressive or bipolar disorder with psychotic features) seasonal affective disorder, a sleep disorder, a specific developmental disorder, agitation disorder, selective serotonin reuptake inhibition (SSRI) xe2x80x9cpoop outxe2x80x9d syndrome or a Tic disorder (e.g., Tourette""s syndrome).
The present invention further provides a method for treating anxiety, depression or stress related disorders comprising administering a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof to the mammal.
The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating or preventing diseases or disorders of the central nervous system.
The present invention further provides a method for modulating 5-HT receptor function, comprising contacting (in vitro or in vivo) the receptor with an effective inhibitory amount of a compound of formula I or a pharmaceutically acceptable salt thereof.
The invention also provides novel intermediates and processes for preparing compounds of formula I.